Proglumide is a drug that has been approved for use in many countries as a treatment for stomach ulcers. It is not approved for use in the United States, and is no longer frequently prescribed internationally, with newer anti-ulcer drugs preferred. Proglumide inhibits gastrointestinal mobility and acts as a cholecystokinin antagonist, blocking both the CCKA and CCKB subtypes.
Cholecystokinin (CCK) is widely distributed in the central nervous system, and its levels increase with chronic opiate administration. Increased levels of CCK are believed to reduce the analgesic effect of opiates, and also are believed to be at least partially responsible for tolerance to opiate analgesics such as morphine.
Since proglumide is a CCK antagonist (albeit a moderate, non-selective one), it has been widely studied for its potential role in enhancing opiate efficacy and/or reducing opiate tolerance. For example, studies have determined that proglumide enhances the analgesic efficacy of morphine in treating human patients with chronic pain (McCleane, G., “The cholecystokinin antagonist proglumide enhances the analgesic efficacy of morphine in humans with chronic benign pain”, Anesth. Analg. (1998) 87:1117-20), and also potentiates morphine analgesia in both opiate-naïve and morphine-tolerant rats (Watkins, L. R. et al., “The enhancement of opiate analgesia and the possible reversal of morphine tolerance by proglumide”, Annals of the New York Academy of Sciences (1985), 448 (Neuronal Cholecystokinin), 676-7). Other studies have observed no difference between treatment and control groups in studies examining whether proglumide augments morphine analgesia in cancer pain management (Bernstein, Z. P. et al., “Proglumide as a morphine adjunct in cancer pain management”, Journal of Pain and Symptom Management (1998), 15(5), 314-20) and in post-operative patients (Lehmann, K. A. et al., “Failure of proglumide, a cholecystokinin antagonist, to potentiate clinical morphine analgesia. A randomized doubleblind postoperative study using patient-controlled analgesia (PCA)”, Anesthesia and Analgesia (1989), 68(1), 51-6).
The placebo effect is a psychobiological phenomenon that is attributable to different mechanisms, including expectation of clinical improvement and Pavlovian conditioning. Endogenous opioids have a significant role in placebo analgesia, although non-opioid mechanisms can also play a significant role (Benedetti, F. et al., “Neurobiological Mechanisms of the Placebo Effect”, Journal of Neuroscience (2005), 25(45): 10390-10402). The effect of endogenous opioids is balanced by the anti-opioid action of CCK. The CCK antagonist proglumide was shown to enhance placebo analgesia (Benedetti, F. et al., “Potentiation of placebo analgesia by proglumide” (1995), Lancet 346: 1231) and block nocebo hyperalgesia (Benedetti, F. et al., “The biochemical and neuroendocrine bases of the hyperalgesic nocebo effect” (2006), Journal of Neuroscience, 26(46):12014-12022).
A significant downside of proglumide is the rapidity with which humans become habituated. While proglumide has been suggested for use in reducing tolerance to opioids, rapid buildup of tolerance to proglumide can be quite problematic. Proglumide has been demonstrated to be ineffective as a long-term adjunct to opiate treatment for chronic pain (Kellstein, D. E., et al., “Chronic administration of cholecystokinin antagonists reverses the enhancement of spinal morphine analgesia induced by acute pretreatment” (1990), Brain Research, 516(2): 263-270). This is unfortunate, as in many cases, a patient's anxiety about chronic pain significantly contributes to the pain experienced by the patient.
While proglumide is a drug that has a good safety record and has a number of interesting properties as described above, it is not approved by FDA. To our knowledge, while proglumide has been suggested as a treatment for other anxiety disorders, it has not been used specifically as a treatment for specific phobia, or administered on a non-chronic basis for the treatment of specific phobias, and moreover, it has not been used as a treatment for fear of medical procedures.